Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia.

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) optimizes the match between ventilation and perfusion in the lung by reducing blood flow to poorly ventilated regions. Sepsis and endotoxemia impair HPV. We previously showed that nitric oxide synthase 2 (NOS2) is required, but not sufficient, for the effect of endotoxin on HPV. The aim of the current study was to identify additional factors that might contribute to the impairment of HPV during endotoxemia. METHODS: Gene expression profiling was determined using pulmonary tissues from NOS2-deficient (NOS2-/-) and wild-type mice subjected to endotoxin or saline challenge (control). HPV was accessed as the percentage increase in left pulmonary vascular resistance (LPVR) in response to left main bronchus occlusion (LMBO) in wild-type mice. RESULTS: Among the 22,690 genes analyzed, endotoxin induced a greater than three-fold increase in 59 and 154 genes in the lungs of wild-type and NOS2-/- mice, respectively. Of all the genes induced by endotoxin in wild-type mice, arginase 1 (Arg1) showed the greatest increase (16.3-fold compared to saline treated wild-type mice). In contrast, endotoxin did not increase expression of Arg1 in NOS2-/- mice. There was no difference in the endotoxin-induced expression of Arg2 between wild-type and NOS2-deficient mice. We investigated the role of arginase in HPV by treating the mice with normal saline or the arginase inhibitor Nω-hydroxy-nor-L-arginine (norNOHA). In control mice (in the absence of endotoxin) treated with normal saline, HPV was intact as determined by profound LMBO-induced increase in LPVR (121 ± 22% from baseline). During endotoxemia and treatment with normal saline, HPV was impaired compared to normal saline treated control mice (33 ± 9% vs. 121 ± 22%, P < 0.05). HPV was restored in endotoxin-exposed mice after treatment with the arginase inhibitor norNOHA as shown by the comparison to endotoxemic mice treated with normal saline (113 ± 29% vs, 33 ± 9%, P < 0.05) and to control mice treated with normal saline (113 ± 29% vs, 121 ± 22%, P = 0.97). CONCLUSIONS: The results of this study suggest that endotoxemia induces Arg1 and that arginase contributes to the endotoxin-induced impairment of HPV in mice.

Search for an animal model to investigate selective pulmonary vasodilation.

Pulmonary arterial hypertension is a life-threatening disease with a poor prognosis. Oral treatment with vasodilators is often limited by systemic hypotension. Inhalation of vasodilators offers the opportunity for selective pulmonary vasodilation. Testing selective pulmonary vasodilation by inhaled nitric oxide or alternative substances in animal models requires an increased pulmonary vascular tone. The aim of this study was to identify animal models that are suitable for investigating selective pulmonary vasodilation. To do so, a haemodynamic stable pulmonary hypertension was initiated, with a 30 min duration deemed to be a sufficient time interval before and after a possible intervention. In anaesthetized and mechanically-ventilated Sprague-Dawley rats pulmonary hypertension was induced either by acute hypoxia due to reduction of the inspired oxygen fraction from 0.21 to 0.1 ( n = 6), a fixed infusion rate of the thromboxane analogue U46619 (240 ng/min; n = 6) or a monocrotaline injection (MCT; 60 mg/kg applied 23 days before the investigation; n = 7). The animals were instrumented to measure right ventricular and systemic arterial pressures. Acute hypoxia caused a short, and only transient, increase of pulmonary artery pressure as well as profound systemic hypotension which suggested haemodynamic instability. U46619 infusion induced variable changes in the pulmonary and systemic vascular tone without sufficient stabilization within 30 min. MCT provoked sustained pulmonary hypertension with normal systemic pressure values and inhalation of nitric oxide caused selective pulmonary vasodilation. In conclusion, out of the three examined rat animal models only MCT-induced pulmonary hypertension is a solid and reliable model for investigating selective pulmonary vasodilation.

Bovine Colostrum Modulates Myeloablative Chemotherapy-Induced Gut Toxicity in Piglets.

BACKGROUND: Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown. OBJECTIVE: We hypothesized that the severity of chemotherapy-induced gut toxicity in early life is diet-dependent, and that intake of bovine colostrum (BC) provides better gut protection than an artificial milk replacer (MR). METHODS: A total of 37 3-d-old pigs received for 6 d either intravenous saline control or myeloablative treatment with busulfan and cyclophosphamide, and were fed either BC or MR, resulting in the following 4 treatments (n = 8-10/group): bovine colostrum plus saline control (Ctr-BC), milk replacer plus saline control (Ctr-MR), bovine colostrum plus busulfan and cyclophosphamide chemotherapy (BUCY-BC), and milk replacer plus busulfan and cyclophosphamide chemotherapy (BUCY-MR). The gut was collected for analysis 11 d after the start of chemotherapy. RESULTS: Relative to the control groups, both busulfan and cyclophosphamide chemotherapy (BUCY) groups showed signs of gut toxicity, with oral ulcers, reduced intestinal dimensions, and hematologic toxicity. Diet type did not affect mucosal structure on day 11, but BUCY-BC pigs had less vomiting than BUCY-MR pigs (1 of 10 vs. 10 of 10, P < 0.05). Markers of intestinal function were higher (up to 20-fold greater galactose absorption and 2-3-fold greater brush border enzyme activity, all P < 0.05), and tissue inflammatory cytokine concentrations and serum liver enzyme values were lower in BUCY-BC than in BUCY-MR pigs (30-50% reductions in interleukin 6 and 8, aminotransferase, and bilirubin concentrations, P < 0.05). Gut colonization was not significantly affected except that BUCY pigs had lower microbial diversity with a higher abundance of Lactobacilli. CONCLUSION: BC may reduce gut toxicity during myeloablative chemotherapy in piglets by preserving intestinal function and reducing inflammation. Whether similar effects occur in children remains to be tested.

[New disease markers within the chronic myeloproliferative neoplasms]. / Nye sygdomsmarkører ved de kroniske myeloproliferative neoplasier.

The chaperone and calcium storing protein calreticulin is coded by CALR, and newly identified mutations in CALR are found in respectively 49-70% and 56-88% of JAK2- and MPL-negative patients with essential thrombocytaemia (ET) and primary myelofibrosis (PMF). A total of 41 mutations have been identified, all located to exon 9 which codes the protein's C-terminal. CALR mutations are present only in myeloid malignancies and confer a more indolent disease than JAK2-mutated ET and PMF. CALR mutations as a diagnostic and prognostic tool are promising and the mutations are potential targets for immune therapy.

Development and validation of a microRNA based diagnostic assay for primary tumor site classification of liver core biopsies.

Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model.

Expression pattern of clinically relevant markers in paediatric germ cell- and sex-cord stromal tumours is similar to adult testicular tumours.

Paediatric germ cell tumours (GCTs) are rare and account for less than 3 % of childhood cancers. Like adult GCTs, they probably originate from primordial germ cells, but the pattern of histopathological types is different, and they occur predominantly in extragonadal sites along the body midline. Because they are rare, histology of paediatric GCTs is poorly documented, and it remains unclear to what extent they differ from adult GCTs. We have analysed 35 paediatric germ cell tumours and 5 gonadal sex-cord stromal tumours from prepubertal patients aged 0-15 years, to gain further knowledge, elaborate on clinical-pathological associations and better understand their developmental divergence. The tumours were screened for expression of stemness-related factors (OCT4, AP-2γ, SOX2), classical yolk sac tumours (YSTs; AFP, SALL4), GCTs (HCG, PLAP, PDPN/D2-40), as well as markers for sex-cord stromal tumour (PDPN, GATA4). All YSTs expressed AFP and SALL4, with GATA4 present in 13/14. The majority of teratomas expressed SOX2 and PDPN, whereas SALL4 was found in 8/13 immature teratomas. Adult seminoma markers AP-2γ, OCT4, SALL4 and PDPN were all expressed in dysgerminoma. We further report a previously unrecognised pathogenetic relationship between AFP and SALL4 in YST in that different populations of YST cells express either SALL4 or AFP, which suggests variable differentiation status. We also show that AP-2γ is expressed in the granulosa layer of ovarian follicles and weakly expressed in immature but not in mature granulosa cell tumours. Our findings indicate that the expression pattern of these antigens is similar between paediatric and adult GCTs, even though they develop along different developmental trajectories.

Adult immunohistochemical markers fail to detect intratubular germ cell neoplasia in prepubertal boys with cryptorchidism.

PURPOSE: Intratubular germ cell neoplasia is a precursor to testicular germ cell cancer. The condition is characterized by large germ cells with large nuclei with a hyperchromatic, coarse chromatin pattern, large prominent nucleoli and abundant pale cytoplasm. In prepubertal boys these cells are located centrally and peripherally mixed with normal cells in the seminiferous tubules. We evaluated the impact of adult intratubular germ cell neoplasia marking immunohistochemistry in screening for intratubular germ cell neoplasia in boys with cryptorchidism. MATERIALS AND METHODS: Histology sections of 236 testicular biopsies were retrieved from 170 boys 1 month to 15 years old operated on for cryptorchidism (excluding disorders of sex development). Specimens were incubated with primary antibodies, including anti-placental-like alkaline phosphatase, anti-Oct3/4, anti-C-kit and anti-D2-40 receptor. RESULTS: A 1-year, 1-month-old boy had intratubular germ cell neoplasia and all positive markers. The prevalence of placental-like alkaline phosphatase positive staining of germ cells in testicular biopsies was 98% in boys younger than 1 year, 82% in those 1 to less than 2 years old, 74% in those 2 to less than 3 years old and 60% in those 3 to 15 years. Similarly the prevalence of C-kit positive staining was 71% in boys younger than 1 year, 49% in those 1 to less than 2 years, 16% in those 2 to less than 3 years and 34% in those 3 to 15 years. Placental-like alkaline phosphatase negative germ cells did not express any of the other described antigens. In none of the 116 testes from boys older than 1 year and 7 months were any Oct3/4 or D2-40 positive germ cells identified. Up to that age 33% and 8% of biopsies were Oct3/4 and D2-40 positive, respectively. CONCLUSIONS: Adult intratubular germ cell neoplasia/cancer immunohistochemical markers cannot be used alone for intratubular germ cell neoplasia screening in male infants with cryptorchidism because positive immunohistochemistry is commonly seen within this age group, when most orchiopexies are performed. It is generally not plausible that intratubular germ cell neoplasia originates during fetal development in patients with cryptorchidism.

Intestinal response to myeloablative chemotherapy in piglets.

Chemotherapy-induced myeloablation prior to allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with severe toxicity. The current understanding of the pathophysiology of oral and gastrointestinal (GI) toxicity is largely derived from studies in rodents and very little is known from humans, especially children. We hypothesized that milk-fed piglets can be used as a clinically relevant model of GI-toxicity related to a standard conditioning chemotherapy (intravenous busulfan, Bu plus cyclophosphamide, Cy) used prior to HSCT. In study 1, dose-response relationships were investigated in three-day-old pigs (Landrace × Yorkshire × Duroc, n = 6). Pigs were given one of three different dose combinations of Bu and Cy (A: 4 days Bu, 2 × 1.6 mg/kg plus 2 days Cy, 60 mg/kg; B: 4 days Bu, 2 × 0.8 mg/kg plus 2 days Cy, 30 mg/kg; C: 2 days Bu at 2 × 1.6 mg/kg plus 1 day Cy, 60 mg/kg) and bone marrow was collected on day 11. Histology of bone marrow samples showed total aplasia after treatment A. Using this treatment in study 2, Bu-Cy pigs showed lowered spleen and intestinal weights and variable clinical signs of dehydration, sepsis, and pneumonia at tissue collection. Oral mucositis was evident as ulcers in the soft palate in 4/9 Bu-Cy pigs and villus height and brush-border enzyme activities were reduced, especially in the proximal intestine. There were no consistent effects on tissue cytokine levels (IL-8, IL-6, IL-1ß, TNF-α) or blood chemistry values (electrolytes, liver transaminases, bilirubin, alkaline phosphatase), except that blood iron levels were higher in Bu-Cy pigs. We conclude that a myeloablative Bu-Cy regimen to piglets results in clinical signs comparable to those seen in pediatric patients subjected to myeloablative treatment prior to HSCT. Piglets may be used as a model for investigating chemotherapy-induced toxicity and dietary and medical interventions.

[Visceral leishmaniasis in two children after vacation in Southern Europe]. / Visceral leishmaniasis hos to børn efter ferie i Sydeuropa.

Pancytopenia, fever and splenomegaly are frequent causes for referrals to paediatric haematology departments, on the suspicion of acute leukaemia. We report two cases of Danish children with the tropical disease visceral leishmaniasis (VL) contracted on short vacations in Southern Europe. One of the patients developed secondary haemophagocytic lymphohistocytosis (HLH). Both children were successfully treated with liposomal amphotericin B. In Denmark, VL is a rare but important differential diagnosis to acute leukaemia and HLH, and should be ruled out after journeys to endemic areas, including Southern Europe.

[Acute, severe liver insufficiency caused by extrahepatic biliary atresia in a newborn]. / Akut, svær leverinsufficiens forårsaget af binyretumor hos nyfødt.

A newborn female was hospitalized due to metabolic acidosis and conjugated hyperbilirubinaemia. Extrahepatic biliary atresia (EHBA) was suspected why a (99m)Tc-mebrofenin cholescintigraphy was performed. It showed poor hepatocyte tracer uptake and no drainage to the gut. The hepatocyte dysfunction was caused by an obstructing adrenal gland neuroblastoma later visualised by ultrasound and MRI. The cholescintigraphy is a non-invasive modality to exclude or confirm the suspicion of EHBA. Furthermore neonatal conjugated hyperbilirubinaemia demands the use of a multimodality imaging strategy for differential diagnosis to EHBA.

Prepubertal unilateral gynecomastia and the presence of 47,XXY mosaicism in breast epithelial cells: a case report.

Breast enlargement in prepubertal boys is a rare condition. This case report describes an otherwise healthy 3-year old non-obese boy who developed a large unilateral cystic breast mass measuring approximately 9 × 6 × 4 cm. The mass was initially treated as a lymphatic malformation, and sclerotherapy with Picibanil (OK-432) was attempted without any detectable effect on size. The mass was later excised. The pathological examination revealed mammary gland tissue suggestive of idiopathic gynecomastia. FISH revealed 47, XXY mosaicism in the abnormal breast epithelial cells, but not in peripheral blood lymphocytes.

The relation between adult dark spermatogonia and other parameters of fertility potential in cryptorchid testes.

PURPOSE: The fertility potential of boys with cryptorchidism may be related to the number of adult dark spermatogonia per tubular transverse section in testicular biopsies taken at orchiopexy. Placental-like alkaline phosphatase positive gonocytes in testes within year 1 of life indicate preserved ability for germ cell transformation. We related these parameters to the total number of tubular germ cells and other factors associated with fertility potential. MATERIALS AND METHODS: The study comprised 89 boys 0.7 to 3 years old (median age 1.8) who underwent bilateral testicular biopsy at bilateral orchiopexy and provided blood samples for gonadotropins and inhibin B. RESULTS: Of 76 boys with adult dark spermatogonia 44 (58%) had a normal mean number of spermatogonia per tubular transverse section compared to 2 of 13 (15%) without adult dark spermatogonia (p <0.05). In the 30 boys with good fertility potential, including a normal mean number of tubular germ cells, and normal gonadotropins and inhibin B, the mean number of adult dark tubular germ cells was 0.081 vs 0.031 in the 38 with low fertility potential, including impaired tubular germ cells and/or low inhibin B but no reactive increase in gonadotropins (p <0.05). In the 21 patients with increased gonadotropins the mean number of adult dark spermatogonia per tubular transverse section was 0.063. Of the 20 boys with normal mean adult dark spermatogonia per tubular transverse section 12 (60%) had good fertility potential, including a normal mean number of tubular germ cells, normal gonadotropins and normal inhibin B, compared to only 18 of 69 (26%) with an impaired mean number of adult dark spermatogonia per tubular transverse section (p <0.05). Of 46 boys with a normal mean number of tubular germ cells 26 (57%) had placental-like alkaline phosphatase positive cells compared to 14 of 43 (33%) with a decreased mean number of tubular germ cells (p <0.05). CONCLUSIONS: The number of placental-like alkaline phosphatase positive gonocytes and adult dark spermatogonia per tubular transverse section are important parameters related to the fertility potential of boys with cryptorchid testes.

Dysregulation of the mitosis-meiosis switch in testicular carcinoma in situ.

Testicular germ cell tumours (TGCT) of young adults arise from the intratubular precursor, carcinoma in situ (CIS). CIS cells are thought to be developmentally arrested and transformed fetal germ cells that survive through childhood and gain invasive capacity after puberty. Given that germ cell neoplasms arise frequently in undervirilized and dysgenetic gonads and the striking physiological difference between meiotic entry in ovaries (fetal life) versus testes (at puberty), this study aimed to investigate whether errors in regulation of meiosis may be implicated in the pathogenesis of CIS or its invasive progression to TGCT. The main focus was on a key sex differentiation and meiosis regulator, DMRT1, which has also been linked to TGCT risk in recent genetic association studies. Expression patterns of DMRT1 and other meiosis regulators (SCP3, DMC1, STRA8, CYP26B1, NANOS2, NANOS3) were investigated in pre- and post-pubertal CIS samples and TGCT by quantitative RT-PCR and immunohistochemistry. The results demonstrated that meiosis markers and meiosis inhibitors were simultaneously expressed in CIS cells, in both pre- and post-pubertal testis samples. DMRT1 was present in a restricted subset of CIS cells, which was relatively greater in pre-pubertal (27%) compared to adult (2.6%) samples. In contrast to the majority of CIS cells, DMRT1-positive CIS cells in adult testes were not proliferating. DMRT1 and most of the other meiosis regulators were absent or expressed at low levels in invasive TGCT, except in spermatocytic seminoma (not derived from CIS). In conclusion, this study indicates that meiosis signalling is dysregulated in CIS cells and that a key regulator of the mitosis-meiosis switch, DMRT1, is expressed in 'early-stage' CIS cells but is down-regulated with further invasive transformation. Whether this mixed meiosis signalling in CIS cells is caused by insufficient virilization of the fetal somatic niche or a partial post-pubertal maturation remains uncertain and requires further study.

Bilateral undescended testes classified according to preoperative and postoperative status of gonadotropins and inhibin B in relation to testicular histopathology at bilateral orchiopexy in infant boys.

PURPOSE: In recent series of boys with cryptorchidism gonadotropin levels have been higher and serum inhibin B levels have been lower than normal. To some extent the serum values of inhibin B reflect the state of germinative epithelium in cryptorchid testes. We evaluated whether blood samples of gonadotropins and inhibin B as well as histopathology could be used to classify undescended testes. MATERIALS AND METHODS: A total of 69 boys (median age 2 years) who underwent surgery for bilateral cryptorchidism had blood samples taken preoperatively and 3 months to 2.1 years postoperatively. Testicular biopsies were performed bilaterally at orchiopexy. The average germ cell number per tubular transverse tubule was measured. RESULTS: Group 1 included 17 patients with increased follicle-stimulating hormone levels. Serum follicle-stimulating hormone and luteinizing hormone decreased significantly after surgery. In 77% of patients (13 of 17) follicle-stimulating hormone levels were normalized. Of these boys 35% (6 of 17) had a low postoperative serum inhibin B. Group 2 consisted of 27 patients with a decreased germ cell number and/or low preoperative inhibin B, but not increased serum follicle-stimulating hormone or luteinizing hormone. There were no significant postoperative changes in follicle-stimulating hormone and luteinizing hormone. Of these boys 22% (6 of 27) had a low serum inhibin B postoperatively. In group 3 there were 25 patients with a normal germ cell number, normal preoperative serum inhibin B and normal gonadotropins. There were no significant changes in luteinizing hormone and follicle-stimulating hormone postoperatively. Only 1 boy in this group had a low postoperative serum inhibin B. CONCLUSIONS: Patients with increased gonadotropin levels may have testicular dysgenesis and some may benefit from early surgery. Patients with normal gonadotropin levels and a decreased germ cell number have transient hypothalamus-pituitary-gonadal hypofunction and a poor fertility prognosis. These patients may benefit from gonadotropin treatment after orchiopexy. Patients with normal gonadotropins, inhibin B and germ cell number have a good fertility prognosis after surgery.

A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to identify the primary tumor site in patients with extracervical carcinoma of unknown primary site.

BACKGROUND: The aim of the present study was to evaluate prospectively the diagnostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and conventional CT regarding the ability to detect the primary tumor site in patients with extracervical metastases from carcinoma of unknown primary (CUP) site. PATIENTS AND METHODS: From January 2006 to December 2010, 136 newly diagnosed CUP patients with extracervical metastases underwent (18)F-FDG PET/CT. A standard of reference (SR) was established by a multidisciplinary team to ensure that the same set of criteria were used for classification of patients, that is, either as CUP patients or patients with a suggested primary tumor site. The independently obtained suggestions of primary tumor sites using PET/CT and CT were correlated with the SR to reach a consensus regarding true-positive (TP), true-negative, false-negative, and false-positive results. RESULTS: SR identified a primary tumor site in 66 CUP patients (48.9%). PET/CT identified 38 TP primary tumor sites and CT identified 43 TP primary tumor sites. No statistically significant differences were observed between (18)F-FDG PET/CT and CT alone in regard to sensitivity, specificity, and accuracy. CONCLUSION: In the general CUP population with multiple extracervical metastases (18)F-FDG PET/CT does not represent a clear diagnostic advantage over CT alone regarding the ability to detect the primary tumor site.

45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function--a retrospective longitudinal study.

CONTEXT: Most previous studies of 45,X/46,XY mosaicism are case reports or have described single aspects of the disease. OBJECTIVE: The objective was to provide longitudinal data of patients with 45,X/46,XY mosaicism. DESIGN: This was a retrospective, longitudinal study conducted from June 1990 to January 2012. SETTING: The study took place at a tertiary pediatric and andrological referral center. PATIENTS OR OTHER PARTICIPANTS: Twenty-five patients (18 boys, seven girls) with 45,X/46,XY mosaicism and its variants were included and were compared to healthy controls. INTERVENTION(S): No interventions were included in the study. MAIN OUTCOME MEASURE(S): Phenotypes were scored using external masculinization scores. Serum LH, FSH, testosterone, estradiol, and inhibin B levels were reported in male patients. IGF-I levels and height were reported in all patients. Available biopsies/gonadectomies were histologically examined. RESULTS: Fourteen of 18 males had external masculinization scores consistent with normal virilization. Ten of 11 male patients experienced spontaneous puberty. Median height sd score was -2.0 (range, -3 to 0.3) for males and -2.2 (range, -2.5 to -1.4) for females, both considerably below genetic potential. Median 1-yr height gain after GH treatment in seven patients was 0.5 sd (0.1 to 1.2). All tissue samples from 15 patients (eight males, seven females) revealed abnormal gonadal histology. Four patients had carcinoma in situ (CIS); two had tissue samples available from early childhood, one showing CIS. CONCLUSIONS: Gonadal function in most 45,X/46,XY males, even those with genital ambiguity, seems sufficient for spontaneous puberty. Short stature and 45,X/46,XY mosaicism seem associated, but patients appear to benefit from GH treatment. Histology from two patients with biopsies from early childhood indicates that CIS originates before puberty.

Radiology, histology and short-term outcome of asymptomatic congenital thoracic malformations.

AIM: The aim of this study was to evaluate the safety and short-term outcome of our management of asymptomatic children with antenatally diagnosed congenital thoracic malformations (CTM), compared with recommendations from a recent review and meta-analysis. METHODS: Twenty-two asymptomatic children with CTM, born in January 1, 2002 to January 8, 2009 were reviewed. Data on complications and respiratory symptoms were collected. RESULTS: No severe respiratory symptoms were recorded. Seventeen children were referred to surgery. Complications were seen in one child. The final diagnoses were congenital pulmonary airway malformation (CPAM) in 13 children, two had sequestrations, and two had other significant malformations. Five children had minor malformations and did not undergo surgery. No malignancies were reported. CONCLUSION: Elective surgery at 1 year of age is safe and carries no apparent risk to asymptomatic children with CTM. The rate of complications was equal to that reported in a recent review and meta-analysis.

Germ cell development in the postnatal testis: the key to prevent malignancy in cryptorchidism?

To permit normal postnatal germ cell development, the mammalian testis undergoes a complex, multi-staged process of descent to the scrotum. Failure of any part of this process leads to congenital cryptorchidism, wherein the malpositioned testis finds itself at the wrong temperature after birth, which leads to secondary germ cell loss and later infertility and risk of cancer. Recent studies suggest that neonatal gonocytes transform into the putative spermatogenic stem cells between 3 and 9 months, and this initial postnatal step is deranged in cryptorchid testes. In addition, it is thought the abnormality high temperature may also impair apoptosis of remaining gonocytes, allowing some to persist to become the possible source of carcinoma in situ and malignancy after puberty. The biology of postnatal germ cell development is of intense interest, as it is likely to be the key to the optimal timing for orchidopexy.

Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence.

BACKGROUND: We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data. METHODS: A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden. RESULTS: Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks. CONCLUSIONS: This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.

Cysteinyl leukotrienes impair hypoxic pulmonary vasoconstriction in endotoxemic mice.

BACKGROUND: Sepsis impairs hypoxic pulmonary vasoconstriction (HPV) in patients and animal models, contributing to systemic hypoxemia. Concentrations of cysteinyl leukotrienes are increased in the bronchoalveolar lavage fluid of patients with sepsis, but the contribution of cysteinyl leukotrienes to the impairment of HPV is unknown. METHODS: Wild-type mice, mice deficient in leukotriene C(4) synthase, the enzyme responsible for cysteinyl leukotriene synthesis, and mice deficient in cysteinyl leukotriene receptor 1 were studied 18 h after challenge with either saline or endotoxin. HPV was measured by the increase in left pulmonary vascular resistance induced by left mainstem bronchus occlusion. Concentrations of cysteinyl leukotrienes were determined in the bronchoalveolar lavage fluid. RESULTS: In the bronchoalveolar lavage fluid of all three strains, cysteinyl leukotrienes were not detectable after saline challenge; whereas endotoxin challenge increased cysteinyl leukotriene concentrations in wild-type mice and mice deficient in cysteinyl leukotriene receptor 1, but not in mice deficient in leukotriene C(4) synthase. HPV did not differ among the three mouse strains after saline challenge (120 ± 26, 114 ± 16, and 115 ± 24%, respectively; mean ± SD). Endotoxin challenge markedly impaired HPV in wild-type mice (41 ± 20%) but only marginally in mice deficient in leukotriene C(4) synthase (96 ± 16%, P < 0.05 vs. wild-type mice), thereby preserving systemic oxygenation. Although endotoxin modestly decreased HPV in mice deficient in cysteinyl leukotriene receptor 1 (80 ± 29%, P < 0.05 vs. saline challenge), the magnitude of impairment was markedly less than in endotoxin-challenged wild-type mice. CONCLUSION: Cysteinyl leukotrienes importantly contribute to endotoxin-induced impairment of HPV in part via a cysteinyl leukotriene receptor 1-dependent mechanism.